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- Bake, Björn, 1939, et al.
(författare)
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Exhaled Particles After a Standardized Breathing Maneuver
- 2017
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Ingår i: Journal of Aerosol Medicine and Pulmonary Drug Delivery. - : Mary Ann Liebert Inc. - 1941-2711 .- 1941-2703. ; 30:4, s. 267-273
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Tidskriftsartikel (refereegranskat)abstract
- Background: Particles in exhaled air (PEx) provide samples of respiratory tract lining fluid from small airways and offer a new opportunity to monitor pathological changes. The exhaled particles are produced by reopening of closed small airways and contain surfactant. The amount of PEx varies by orders of magnitude among subjects. A standardized breathing pattern reduces the variation, but it remains large and the reasons are unknown. The aim of the present study was to assess to what extent sex, age, body size, and spirometry results explain the interindividual variation of PEx among healthy middle-aged subjects. Methods: The PExA((R)) instrument was used to measure PEx in 126 healthy middle-aged nonsmoking subjects participating in the European Respiratory Community Health Survey (ERCS-III). The subjects performed a standardized breathing maneuver involving expiration to residual volume, a breath-hold of 3 seconds, a full inspiration, and then a full expiration into the PExA instrument. PEx number concentrations were expressed per exhalation and per exhaled liter. Age and anthropometric and spirometric variables were analyzed as potential predictors. Results: PEx/L was consistently and negatively associated to lung size-related variables and accordingly lower in men than in women. PEx/Exhalation was similar in women and men. Increasing age was associated with increasing PEx. Reference equations are presented based on age, weight, and spirometry variables and independent of sex. These predictors explained 28%-29% of the interindividual variation. Conclusions: The interindividual variation of PEx after a standardized breathing maneuver is large and the considered predictors explain a minor part only.
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| 4. |
- Boger, Elin, et al.
(författare)
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Physiologically Based Pharmacokinetic/Pharmacodynamic Modeling Accurately Predicts the Better Bronchodilatory Effect of Inhaled Versus Oral Salbutamol Dosage Forms
- 2018
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Ingår i: Journal of Aerosol Medicine. - : MARY ANN LIEBERT, INC. - 1941-2711 .- 1941-2703. ; 31:0, s. 1-12
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Tidskriftsartikel (refereegranskat)abstract
- Background: Predicting local lung tissue pharmacodynamic (PD) responses of inhaled drugs is a longstanding challenge related to the lack of experimental techniques to determine local free drug concentrations. This has prompted the use of physiologically based pharmacokinetic (PBPK) modeling to potentially predict local concentration and response. A unique opportunity for PBPK model evaluation is provided by the clinical PD data for salbutamol, which in its inhaled dosage form (400g), produces a higher bronchodilatory effect than in its oral dosage form (2mg) despite lower drug concentrations in blood. The present study aimed at evaluating whether inhalation PBPK model predictions of free drug in tissue would be predictive of these observations.Methods: A PBPK model, including 24 airway generations, was parameterized to describe lung, plasma, and epithelial lining fluid concentrations of salbutamol administered intratracheally and intravenously to rats (100nmol/kg). Plasma and lung tissue concentrations of unbound (R)-salbutamol, the active enantiomer, were predicted with a humanized version of the model and related to effect in terms of forced expiratory volume in 1 second (FEV1).Results: In contrast to oral dosing, the model predicted inhalation to result in spatial heterogeneity in the target site concentrations (subepithelium) with higher free drug concentrations in the lung as compared with the plasma. FEV1 of inhaled salbutamol was accurately predicted from the PK/PD relationship derived from oral salbutamol and PBPK predictions of free concentration in airway tissue of high resistance (e.g., 6th generation).Conclusion: An inhalation PBPK-PD model was developed and shown predictive of local pharmacology of inhaled salbutamol, thus conceptually demonstrating the validity of PBPK model predictions of free drug concentrations in lung tissue. This achievement unlocks the power of inhalation PBPK modeling to interrogate local pharmacology and guide optimization and development of inhaled drugs and their formulations.
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- Elihn, Karine, et al.
(författare)
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Cellular Dose of Partly Soluble Cu Particle Aerosols at the Air-Liquid Interface Using an In Vitro Lung Cell Exposure System
- 2013
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Ingår i: Journal of Aerosol Medicine. - : Mary Ann Liebert Inc. - 1941-2711 .- 1941-2703. ; 26:2, s. 84-93
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Tidskriftsartikel (refereegranskat)abstract
- Background: There is currently a need to develop and test in vitro systems for predicting the toxicity of nanoparticles. One challenge is to determine the actual cellular dose of nanoparticles after exposure. Methods: In this study, human epithelial lung cells (A549) were exposed to airborne Cu particles at the air-liquid interface (ALI). The cellular dose was determined for two different particle sizes at different deposition conditions, including constant and pulsed Cu aerosol flow. Results: Airborne polydisperse particles with a geometric mean diameter (GMD) of 180nm [geometric standard deviation (GSD) 1.5, concentration 10(5) particles/mL] deposited at the ALI yielded a cellular dose of 0.4-2.6 mu g/cm(2) at pulsed flow and 1.6-7.6 mu g/cm(2) at constant flow. Smaller polydisperse particles in the nanoregime (GMD 80 nm, GSD 1.5, concentration 10(7) particles/mL) resulted in a lower cellular dose of 0.01-0.05 mu g/cm(2) at pulsed flow, whereas no deposition was observed at constant flow. Exposure experiments with and without cells showed that the Cu particles were partly dissolved upon deposition on cells and in contact with medium. Conclusions: Different cellular doses were obtained for the different Cu particle sizes (generated with different methods). Furthermore, the cellular doses were affected by the flow conditions in the cell exposure system and the solubility of Cu. The cellular doses of Cu presented here are the amount of Cu that remained on the cells after completion of an experiment. As Cu particles were partly dissolved, Cu (a nonnegligible contribution) was, in addition, present and analyzed in the nourishing medium present beneath the cells. This study presents cellular doses induced by Cu particles and demonstrates difficulties with deposition of nanoparticles at the ALI and of partially soluble particles.
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